Geigy Corporation (Dill et al., 1982) as the fifth commercially developed herbicide antidote. CGA-92194 is also a grain sorghum protectant against

metolachlor injury. A brief summary of the major events that played a key role in

the development of herbicide antidotes is given in Table III.

B.

SEARCH FOR

HERBICIDE'

ANTIDOTES

I . Important Considerations

In general, the process of discovering and developing effective herbicide

antidotes resembles very much that of the commercial development of herbicides. Both of these processes are quite lengthy and very expensive, primarily

because of the increased governmental clearance requirements regulating

pesticide registration. The use of random screening techniques has been long

recognized as the preferred approach of the herbicide industry in finding and

evaluating candidate chemicals as herbicides. The selection of candidate chemicals for inclusion in screening tests evaluating herbicidal activity can be based on

three main methods, known as the empirical, imitative, and rational methods

(Saggers, 1976). The empirical method is based on experiment and observation

and includes the synthesis or acquisition of a large number of novel compounds

with unknown biological properties, which are tested for possible activity. Commonly, one compound for each 12,000 or more screened is developed commercially as a herbicide (Krzeminski and Ryan, 1980). However, this method is very

popular in spite of its low ratio of success because of its excellent chances for

exclusive patentability of discovered active compounds. The imitative method is

based on the synthesis of derivatives or analogs of existing compounds with

known biological activity and selectivity. Obviously, this method has a much

higher ratio of success than the empirical method, but its potential for exclusive

patentability of discovered active chemicals is very limited. The third method,

known as the rational method, is based on the selection of compounds that have

been specifically synthesized to interfere with a desired biochemical or physiological plant process. Application of this method in herbicide development has

been very limited.

Random screening techniques based primarily on the empirical and to a lesser

extent on the imitative method of selecting candidate chemicals also have been

instrumental in the commercial development of herbicide antidotes. Herbicide

antidoting, however, is very much dependent on the specific interactions of three

main factors; the crop to be protected, the herbicide to be antidoted, and the

potential antidote. Furthermore, because a desirable screening program for candidate antidotes must be economical, the program has to be selective as to the

crops and herbicides that need to be considered. The primary screening tests for

herbicide antidotes should involve most combinations of important herbicides,

274

W O N K. HATZIOS

possible antidotes, and major crops. On a worldwide basis, the major crops of

oats, rye, sugar beets, potato, and alfalfa. A number of selective herbicides are

already available for controlling problem weeds in these crops and there is no

doubt that new ones will be developed in the future. However, as the weed

complexes affecting any given crop are in continual change and new weed

problems develop as existing problems are solved, the need for alternative herbicides to deal with these new weed problems continues. Alternative herbicides

to control weeds that have developed resistance to triazine herbicides are very

much needed at the present time for weed control programs in corn. Weeds that

bear a very close botanical relationship to a given crop have always been difficult

to control because the existing herbicides that are effective in controlling them

are frequently injurious to the respective crops. The problem is exemplified by

our limited success in the chemical control of wild oats in cultivated oats,

shattercane in cultivated grain sorghum, and wild rice in cultivated rice. Herbicides and crops in this kind of situation need to be seriously considered for

inclusion in screening programs of candidate antidotes. Most of the success in

developing herbicide antidotes has been with antidoting such herbicides on several grass crops (Blair et al., 1976; Pallos and Casida, 1978; Parker, 1983).

Candidate antidotes that are effective in protecting one or more major crops

against one or more important herbicides are identified in the so-called primary

antidote screen. This process includes laboratory and greenhouse multiple

crop-multiple herbicide screening assays and a large number of candidate antidotes. The antidotes that show promise in the primary screen are further evaluated for their practical value under field conditions in the so-called secondary

antidote screen. The most important properties of an antidote that are considered

during this stage are selectivity, optimum rates for antidotal activity, antidote-toherbicide dosage ratios, suitability of active material for practical fomulations,

and reliability of the antidote under field conditions. A herbicide antidote is said

to be selective when it counteracts herbicides only on crop plants and not on

weed species. In practice, the selectivity of herbicide antidotes is primarily the

result of a selective placement, which usually is the coating of crop seeds with

the antidote. Thus, coating of corn and grain sorghum seeds with the herbicide

antidotes NA and CGA-43089 offers sufficient protection to these crops against

injury from the herbicides EFTC and metolachlor, respectively, without protecting any weeds. In some cases, however, the selectivity of a herbicide antidote

could be the result of a very specific crop-herbicide-antidote interaction such as

occurs with corn-EFTC-R-25788. Broadcast application of the antidote

R-25788 offers good protection against EFTC injury only to corn and not to any

other grass or broad-leaved weeds that are present in the field (Stephenson and

Chang, 1978). Eventually, it is the suitability of a candidate antidote for practical

use in the field that determines whether or not this compound will be further

developed commercially. Several of the important considerations for the evalua-

HERBICIDE ANTIDOTES

275

tion and development of candidate antidotes are discussed briefly in the next

section.

2. Screening of Candidate Antidotes

a. Antidotes for Chloroacetanilide and ThiocarbamateHerbicides. The first

empirical screening tests of candidate herbicide antidotes were conducted by

Hoffman (1962, 1978a), who found that with the exception of herbicides that

inhibit photosynthesis at photosystem II, most of the important herbicides could

be antidoted to some extent on some crop. By using multiple crop-multiple

herbicide screening assays, Hoffman showed that the tolerance of all grass crops

to chloroacetanilideor thiocarbamate herbicides could be enhanced chemically to

some extent. In particular, the chloroacetanilide herbicide alachlor could be